# Enhancing miRNA Therapeutics through Combinatorial Targeting and Vehicle Free Delivery

> **NIH NIH R01** · PURDUE UNIVERSITY · 2020 · $354,563

## Abstract

MicroRNAs (miRNAs) have emerged as powerful regulators of the genome and, through concerted efforts to
identify their function and evaluate their ability to alter cell growth in vitro and in vivo, some have gained favor
as potential therapeutics. Although these miRNA-based approaches can revolutionize the way that tumors are
diagnosed and treated, our understanding of the functional and the molecular aspects of miRNA biology are
still incomplete. Moreover, in order to bridge miRNA biology with clinical utility, the challenges that still remain
with regard to in vivo delivery of miRNAs must be tackled. To address these challenges we propose two
Specific Aims: I. To enhance miRNA therapeutic efficacy through combinatorial miRNA-based targeting and
molecular profiling and II. To develop and test second-generation vehicles for delivery of unprotected miRNAs.
 Our extensive preliminary evidence supports both Aims. We recently identified 10 miRNAs out of 2,019
that significantly enhance the tumor suppressive activity of miR-34a, the first miRNA to enter into clinical trial,
and have begun to identify the direct targets of these miRNAs to gain insight into the molecular reason for the
cooperative effect. We used a novel method that relies on ligating the cellular miRNAs directly to their
associated RNA target followed by deep sequencing of the RNA hybrids. The sequencing data from 13
libraries that we constructed will be used to identify the direct targets of these miRNAs, independent of current
algorithms. Targets will be validated and evaluated for pathways that they associate with that will begin to
explain their cooperative effect with miR-34a. We also propose to evaluate the in vivo efficacy of the
combinatorial pairs using various models of lung cancer. Although we are committed to understanding how
these miRNAs are cooperating with miR-34a we also propose to use this data to better understand miRNA
biology at a global level. Thus, our data will be used to determine how miRNAs associate with their targets at
nucleotide resolution, and how the target population changes with regard to miRNA concentration, which is
extremely important to understand as miRNA clinical utility increases. In parallel we will develop and test a
second-generation miRNA delivery vehicle, which is a first-in-class method for delivering miRNAs completely
unprotected. Following systemic delivery using this method, the miRNA accumulates specifically in the tumor
and is efficiently taken up by the tumorigenic cells as indicated by target gene repression with no obvious
toxicity. Collectively, the data obtained from this work will validate in vivo efficacy for combinatorial miRNA
therapeutics, and for the first time will provide evidence for unprotected miRNA delivery. We will also begin to
break down the barriers regarding miRNA target identification that until now has been mostly approached using
algorithms that lack critical parameters due to a gap in our understanding of how ...

## Key facts

- **NIH application ID:** 9999950
- **Project number:** 5R01CA205420-04
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Andrea L Kasinski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,563
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999950

## Citation

> US National Institutes of Health, RePORTER application 9999950, Enhancing miRNA Therapeutics through Combinatorial Targeting and Vehicle Free Delivery (5R01CA205420-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9999950. Licensed CC0.

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